Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis.

Xu, Duo; Liang, Shun-Qing; Yang, Zhang; Yang, Haitang; Bruggmann, Rémy; Oberhaensli, Simone; Berezowska, Sabina; Marti, Thomas M; Hall, Sean R R; Dorn, Patrick; Kocher, Gregor J; Schmid, Ralph A; Peng, Ren-Wang (2021). Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis. Cell death & disease, 12(4), p. 406. Nature Publishing Group 10.1038/s41419-021-03668-x

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Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients' tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Xu, Duo; Yang, Zhang; Yang, Haitang; Bruggmann, Rémy; Oberhänsli, Simone; Berezowska, Sabina Anna; Marti, Thomas; Hall, Sean; Dorn, Patrick; Kocher, Gregor; Schmid, Ralph and Peng, Ren-Wang

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2041-4889

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

06 Jul 2021 16:46

Last Modified:

11 Jul 2021 03:12

Publisher DOI:

10.1038/s41419-021-03668-x

PubMed ID:

33859162

BORIS DOI:

10.48350/157379

URI:

https://boris.unibe.ch/id/eprint/157379

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